Effects of N-methyl-D-aspartate receptor antagonism on neuroleptic-induced orofacial dyskinesias.

RATIONALE: Tardive dyskinesia is a syndrome of abnormal, involuntary movements, which occurs as a complication of long-term neuroleptic therapy. The pathophysiology of this potentially irreversible syndrome is still an enigma. OBJECTIVE: The objective of the present study was to elucidate the role of N-methyl-D-aspartate (NMDA) receptor involvement in neuroleptic-induced orofacial dyskinesia in rats. METHODS: Animals chronically treated with haloperidol for a period of 40 weeks exhibited significantly more vacuous chewing movements (VCMs), as compared to vehicle-treated controls. In a series of acute experiments, rats received: amantadine (10, 20, and 40 mg/kg i.p.), a low-affinity, uncompetitive NMDA-receptor antagonist (open channel blocker); dextrorphan (5, 10, and 20 mg/kg i.p.), an NMDA receptor channel antagonist; ifenprodil (2.5, 5, and 10 mg/kg i.p.), a noncompetitive allosteric NMDA receptor antagonist acting at the polyamine site; and Ro 25-6981 (2.5, 5, and 10 mg/kg i.p.), a potent and selective blocker of NMDA receptors which contain the NR2B subunit. RESULTS: All the drugs tested, except dextrorphan, reduced VCMs and tongue protrusions with varying efficacies and side effects profiles. Ro 25-6981 was found significantly more potent than amantadine and ifenprodil in reducing VCMs and tongue protrusions at all doses tested, and at the higher dose, it completely eliminated orofacial dyskinesia (p<0.05). CONCLUSIONS: These results suggest that NMDA receptors may play a significant role in the pathophysiology of tardive dyskinesia. Furthermore, antagonists showing selectivity for NMDA receptors containing the NR2B subunit may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further testing.

Intravenous dextromethorphan to human volunteers: relationship between pharmacokinetics and anti-hyperalgesic effect.

The aim of this study was to investigate the effect of dextromethorphan (DM) 0.5 mg/kg administered intravenously (i.v.) on hyperalgesia and pain after a tissue injury in human volunteers, and to describe the relationship between pharmacokinetic and pharmacodynamic data. The heat-capsaicin sensitisation model, a well-established experimental hyperalgesia model was induced in 24 healthy, male volunteers aged 21-35 years. The subjects received i.v. DM 0.5 mg/kg or isotonic saline on two separate study sessions. The primary outcome measure from 0 to 3 h was reduction in area of established secondary hyperalgesia. Secondary outcome measures were reduction in area of secondary hyperalgesia in response to brief thermal stimulation, heat pain detection thresholds and painfulness after tonic heat pain. Blood samples were collected throughout the study to describe the relationship between pharmacokinetic and pharmacodynamic data. Intravenous DM 0.5 mg/kg significantly reduced areas of established secondary hyperalgesia with an average of 39% (P<0.05). Development of secondary hyperalgesia was substantially prevented by DM (P<0.05). No significant effect was seen on either heat pain detection thresholds or after tonic heat pain. The pharmacokinetic-pharmacodynamic relationship showed a large inter-subject variation with a mean delay in effect of nearly 2 h in relation to peak serum concentration. The results strongly indicate that DM is an anti-hyperalgesic drug. The delay in effect may be explained by several mechanisms and suggests that timing of DM administration is an essential factor for using the drug in clinical settings.

Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant activity against kainate in mice.

The effects of dextromethorphan (DM), and its major metabolite dextrorphan (DX) on kainic acid-induced seizures in mice were examined. Intracerebroventricular DM or DX (5 or 10 microg/0.5 microl) pretreatment significantly attenuated seizures induced by kainic acid (0.07 microg/0.07 microl) in a dose-related manner. DM or DX pretreatment significantly attenuated kainic acid-induced increases in AP-1 DNA-binding activity and fos-related antigen-immunoreactivity as well as neuronal loss in the hippocampus. DM appears to be a more potent neuroprotectant than DX. Since the high-affinity DM binding sites are recognized as being identical to the sigma-1 site, we examined the role of the sigma-1 receptor on the pharmacological action mediated by DM or DX. Pretreatment with the sigma-1 receptor antagonist BD1047 (2.5 or 5 mg/kg, i.p.) blocked the neuroprotection by DM in a dose-related manner. This effect of BD 1047 was more pronounced in the animals treated with DM than in those treated with DX. Combined, our results suggest that metabolism of DM to DX is not essential for DM to exert its effect. They also suggest that DM provides neuroprotection from kainic acid via sigma-1 receptor modulation.

Reduction of ischemic spinal cord injury by dextrorphan: comparison of several methods of administration.

OBJECTIVES: We investigated the effect of dextrorphan, an N -methyl-D -aspartate receptor antagonist, on the reduction of ischemic spinal cord injury and the safe clamping time after various methods of administration. METHODS: Spinal cord ischemia was induced in New Zealand White rabbits by infrarenal aortic clamping and animals were divided into 5 groups. Group A (n = 15) received simple clamping. Groups B (n = 20) and C (n = 35) received dextrorphan pretreatment (10 mg/kg), followed by continuous intravenous or intra-aortic infusion (1 mg/min), respectively. Group D (n = 25) received the same dextrorphan pretreatment and bolus intra-aortic injection at clamping (1 mg per minute of clamping time). Group E (n = 15) received bolus intrathecal injection of dextrorphan (0.2 mg/kg). Each dextrorphan-treated group had a small group of control animals (n = 5). The neurologic status was assessed by the Johnson score (5 = normal, 0 = paraplegic) 48 hours after unclamping, and animals were put to death for histopathologic examination. RESULTS: All dextrorphan-treated groups showed better neurologic function than the respective control animals (P <.001 vs groups B, C, and D; P =.014 vs group E). The order of efficacy of dextrorphan (as revealed by the average of neurologic status) was as follows: group C > group D (P =.017, after 50 minutes of clamping), group D > group B (P =.014, after 45 minutes of clamping), and group B > group E (P <.001, after 40 minutes of clamping). Histopathologic findings did not necessarily correspond with hind-limb neurologic function. CONCLUSIONS: Dextrorphan reduced the physical findings associated with ischemic spinal cord injury, and continuous intra-aortic infusion prolonged the safe clamping time significantly more than delivery by other routes.

Dextromethorphan and dextrorphan in rats: common antitussives--different behavioural profiles.

Dextromethorphan (DM), a widely used and well-tolerated centrally acting antitussive, has been tested in several clinical trials for its antiepileptic and neuroprotective properties. However, the use of DM in these new clinical indications requires higher doses than antitussive doses, which may therefore induce phencyclidine (PCP)-like side-effects (memory and psychotomimetic disturbances) through its metabolic conversion to the active metabolite dextrorphan (DX), a more potent PCP-like non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor than DM. Thus, we compared the behavioural effects in rats of intraperitoneal administration of DM and DX on motor activity in an open field and on learning and memory in the Morris water maze. DM (20, 30, 40 mg/kg) produced a dose-dependent decrease in both locomotion and stereotyped behaviour with a slight ataxia for the highest dose. DX (20, 30, 40 mg/kg) induced a dose-dependent increase in locomotion and stereotypies (swaying, turning) with moderate ataxia. Assessments of learning and memory were performed with lower doses of DM (10, 20, 30 mg/kg) and DX (5, 10, 15 mg/kg) because of motivational deficits (40 mg/kg of DM, 20-40 mg/kg of DX) and motor disorders (30, 40 mg/kg of DX) in the cue learning procedure. DX (10, 15 mg/kg) impaired spatial learning with a long-lasting effect for the highest dose whereas 5 mg/kg of DX and DM (10-30 mg/kg) did not. Only 15 mg/kg of DX appeared to slightly impair working memory. DM (10-30 mg/kg) and DX (5-15 mg/kg) did not impair reference memory. Thus, the two antitussives DM and DX induced different behavioural effects suggesting sedative effects for DM and PCP-like effects for DX. However, PCP-like side-effects with DM remain possible through its metabolic conversion to DX, with very high doses and/or in extensive metabolizers and/or in aged subjects prone to cognitive dysfunction. Therefore, the identification of DM metabolism phenotype, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects.

Effects of N-methyl-D-aspartate antagonists on different measures of motion sickness in cats.

Because N-methyl-D-aspartate (NMDA) antagonists prevent cisplatin-induced emesis and NMDA receptors are in both emetic pathways and structures associated with the final common pathway for vomiting, they have the potential to be broad-spectrum antiemetics. This was evaluated by determining their effects on motion sickness in cats. The measures included the number vomiting, the number of symptom points, which reflect activity early in the final common path and the duration of the retch/vomit sequence, which reflects activity late in the path. Dextrorphan, ketamine and dextromethorphan decreased the number vomiting with the same rank order of potency as at NMDA receptors. Additional studies with 1,3-dio-tolylguaninidine (DTG) and haloperidol ruled out a role for sigma receptors. The NMDA antagonists produced a nonsignificant dose-dependent decrease in symptoms and had no effects on the duration of vomiting. They also produced motor abnormalities at the highest doses. The competitive antagonist LY 233053 also decreased the number vomiting without altering the duration. It produced a nonsignificant non-dose-dependent decrease in symptoms and had no effects on gross motor output. The results are consistent with a broad spectrum of antiemetic efficacy with at least a part of its action in the early to middle portions of the final common pathway for vomiting. Additional actions on the vestibular nuclei are possible.

Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson's disease.

In animal models of Parkinson's disease (PD), glutamate antagonists diminish levodopa (LD)-associated motor fluctuations and dyskinesias. We sought to investigate if these preclinical observations can be extended to the human disease, by evaluating the effects of three non-competitive NMDA antagonists (dextrorphan, dextromethorphan and amantadine) on the motor response to LD in patients with advanced PD. In four separate trials, adjuvant therapy with these drugs reduced LD-induced dyskinesias and motor fluctuations. These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate LD associated motor response complications.

Evaluation of dextromethorphan and dextrorphan as a preventive treatment of soman toxicity in mice.

Phencyclidine-like drugs are effective against convulsions and brain lesions related to soman intoxication but induce severe side effects. The well tolerated antitussive dextromethorphan (DM) and its metabolite dextrorphan (DX) have antiepileptic and neuroprotective properties that we evaluated in mice against 2 LD50 of soman in a three-drug pretreatment (atropine sulfate and oxime HI-6 plus DM: 20-50 mg/kg or DX: 10-40 mg/kg i.p). Neuroprotection was evaluated by measurement of hippocampal omega 3 binding site density. DM and DX have weak anticonvulsant and neuroprotective activities which are counterbalanced at high doses by an increased mortality due to respiratory distress for DM and by ataxia for DX. Thus DM and DX do not appear to be appropriate for the pretreatment of soman intoxication.

Protection of rat spinal cord from ischemia with dextrorphan and cycloheximide: effects on necrosis and apoptosis.

OBJECTIVE: We examined the characteristics of neuronal cell death after transient spinal cord ischemia in the rat and the effects of an N-methyl-D-aspartate antagonist, dextrorphan, and a protein synthesis inhibitor, cycloheximide. METHODS: Spinal cord ischemia was induced for 15 minutes in Long-Evans rats with use of a 2F Fogarty catheter, which was passed through the left carotid artery and occluded the descending aorta, combined with a blood volume reduction distal to the occlusion. The rats were killed after 1, 2, and 7 days. Other groups of rats were pretreated with dextrorphan (30 mg/kg, intraperitoneally, n = 7), cycloheximide (30 mg, intrathecally, n = 7), or vehicle (saline solution, n = 12) and killed after 2 days. RESULTS: This model reliably produced paraplegia and histopathologically distinct morphologic changes consistent with necrosis or apoptosis by light and electron microscopic criteria in different neuronal populations in the lumbar cord. Scattered necrotic neurons were seen in the intermediate gray matter (laminae 3 to 7) after 1, 2, and 7 days, whereas apoptotic neurons were seen in the dorsal horn laminae 1 to 3 after 1 and 2 days. Deoxyribonucleic acid extracted from lumbar cord showed internucleosomal fragmentation (laddering) on gel electrophoresis indicative of apoptosis. The severity of paraplegia in the rats treated with dextrorphan and cycloheximide was attenuated 1 day and 2 days after ischemia. The numbers of both necrotic and apoptotic neurons were markedly reduced in both dextrorphan- and cycloheximide-treated rats. CONCLUSIONS: The results suggest that both N-methyl-D-aspartate receptor-mediated excitotoxicity and apoptosis contribute to spinal cord neuronal death after ischemia and that pharmacologic treatments directed at blocking both of these processes may have therapeutic utility in reducing spinal cord ischemic injury.

Dextrorphan, but not dextromethorphan, exerts weak antidystonic effects in mutant dystonic hamsters.

The effects of dextromethorphan and its metabolite dextrorphan on severity of dystonia were examined in mutant dystonic hamsters, an animal model of idiopathic paroxysmal dystonia, in which recent examinations have shown antidystonic effects of selective N-methyl-D-aspartate (NMDA) receptor antagonists. Dextromethorphan and dextrorphan are non-competitive NMDA receptor antagonists which additionally exhibit affinity for sigma receptors. Dextrorphan (20 and 40 mg/kg i.p.) significantly retarded the progression of dystonia at the higher dose, whereas dextromethorphan (20, 40, 60 mg/kg i.p.) failed to exert any antidystonic effects even at high doses which caused severe effects. The lack of antidystonic efficacy of dextromethorphan may be related to its higher affinity to sigma receptors compared with dextrorphan.

Dextrorphan reduces infarct volume, vascular injury, and brain edema after ischemic brain injury.

Focal cerebral ischemia confined to the cerebral cortex in the right middle cerebral artery (MCA) territory was induced by temporary ligation of the MCA and both common carotid arteries (CCAs). Reperfusion was initiated by releasing all three arterial occlusions after 90 min of ischemia. Infarct volume was morphometrically measured after triphenyltetrazolium chloride staining 24 h postischemia. Blood-brain barrier breakdown was assessed 4 h postischemia by measuring vascular permeability to fluorescein isothiocyanate-conjugated dextran (FITC-D), a macromolecule tracer. Ischemic brain edema was measured based on percent water content, 24 h postischemia. Dextrorphan (DX) 20-10 mg/kg given ip 15 min before ischemia reduced infarct volume in a dose-dependent manner with an apparent U-shaped dose-response curve; best protection was observed at 30 mg/kg. Posttreatment at 30 min, but not 60 min, was still effective. DX (30 mg/kg, given 15 min before ischemia) also reduced the postischemic increase in vascular permeability and brain edema in the right MCA cortex. Results from this study support the idea that NMDA receptor activation contributes to blood-brain barrier breakdown and brain edema after ischemic insults

Safety, tolerability and pharmacokinetics of the N-methyl-D-aspartate antagonist Ro-01-6794/706 in patients with acute ischemic stroke. The Dextrorphan Study Group and Hoffmann-La Roche.

Dextrorphan HCl (Ro 01-6794/706) is an NMDA receptor antagonist with clinical potential for administration in an elderly population of acute ischemic stroke patients. In vivo experience with such patients demonstrated a consistent pharmacologic effect/adverse experience profile that is typical of an NMDA receptor antagonist (e.g., nystagmus, nausea, vomiting, agitation, somnolence, hallucinations and hypertension). For the most part, these pharmacologic effects were mild to moderate in severity; short-lived; reversible; not life-threatening and subjectively tolerated. The most serious pharmacologic effect produced by dextrorphan administration was hypotension, which occurred within a well-defined window of 90 minutes from the start of the loading dose infusion in patients who received 200 mg/hr or greater loading dose infusions. In all cases it was reversible without neurologic sequelae. Careful review of demographic and pharmacokinetic parameters did not demonstrate any overriding factor(s) to the production of hypotension other than the rate of the loading dose infusion. Severe hypotension, severe decreased levels of consciousness and respiratory depression should not be generally expected at loading doses less than 200 mg/hr. In summary, dextrorphan can be safely given to an elderly population of ischemic stroke patients as a loading dose rate below 200 mg/hr and as a maintenance dose rate between 50-90 mg/hr for 24 hours when patients are monitored carefully for pharmacologic effects.

Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group.

BACKGROUND AND PURPOSE: Dextrorphan hydrochloride is a noncompetitive N-methyl-D-aspartate antagonist that is neuroprotective in experimental models of focal brain ischemia. The purpose of this study was to determine the maximum loading dose and maintenance infusion of dextrorphan hydrochloride that are well tolerated in patients with an acute stroke. METHODS: An intravenous infusion of dextrorphan or placebo was begun within 48 hours of onset of a mild-to-moderate hemispheric stroke. Initially, patients were treated with either placebo (n = 15) or dextrorphan (n = 22) using a 1-hour loading dose (60 to 150 mg) followed by a 23-hour ascending-dose maintenance infusion (maximum total dose, 3310 mg). Subsequently, 29 patients were treated with dextrorphan in an open trial using a 1-hour loading dose (145 to 260 mg) followed by an 11-hour constant rate (30 to 70 mg/h) infusion. RESULTS: Transient and reversible adverse effects, including nystagmus, nausea, vomiting, somnolence, hallucinations, and agitation, commonly occurred in dextrorphan-treated patients. Loading-dose escalation was stopped because of rapid-onset, reversible, symptomatic hypotension in 7 of 21 patients treated with doses of 200 to 260 mg/h. At the highest rates of maintenance infusion (> 90 mg/h), 3 patients developed deep stupor or apnea. The maximum tolerated loading dose was 180 mg/h, and the maximum tolerated maintenance infusion was 70 mg/h. Maximum plasma levels of 750 to 1000 ng/mL were obtained in 9 patients. There was no difference in neurological outcome at 48 hours between the dextrorphan-treated and placebo-treated patients. CONCLUSIONS: The highest doses of dextrorphan administered were associated with serious adverse experiences in some patients. Lower doses (loading doses of 145 to 180 mg, maintenance infusions of 50 to 70 mg/h) were better tolerated and rapidly produced potentially neuroprotective plasma concentrations of dextrorphan. These doses were associated with well-defined pharmacological effects compatible with N-methyl-D-aspartate receptor antagonism.

Dextromethorphan: cellular effects reducing neuronal hyperactivity.

Dextromethorphan is a dextrorotary morphinan without affinity for opioid receptors, commonly used as an antitussive medication. During the past 5 years, interest in the compound and its demethylated derivative, dextrorphan, has been revived because additional neuroprotective and antiepileptic properties were found in in vitro studies, animal experiments, and a few clinical cases. Both morphinans are able to inhibit N-methyl-D-aspartate (NMDA) receptor channels and voltage-operated calcium and sodium channels with different potencies. The inhibition of the NMDA receptor is believed to be the predominant mechanism of action responsible for the anticonvulsant and neuroprotective properties of the compounds.

A dose-response study of dextrorphan in permanent focal ischemia.

The dose-response curve and time window of efficacy for dextrorphan in permanent focal brain ischemia leading to infarction was studied in the rat. With pretreatment, the maximum effective dose of 20 mg/kg reduced the eventual infarct volume by greater than 50%. Delayed drug administration, up to 45 min following permanent middle cerebral artery occlusion, significantly reduced infarct size.

Dextrorphan relieves neuropathic heat-evoked hyperalgesia in the rat.

Dextrorphan (DEX), a non-competitive NMDA receptor antagonist, was given intraperitoneally and intrathecally (i.t.) to rats with an experimental painful peripheral mononeuropathy. The neuropathy was created by placing loosely constrictive ligatures around the sciatic nerve, and the pain threshold was studied with the paw-flick method. The effects of DEX on the neuropathic heat-evoked hyperalgesia that follows this nerve injury were determined during the period of peak symptom severity. DEX given i.p. relieved heat-evoked hyperalgesia in a dose-dependent manner without producing motor impairment. The highest doses tested (12.5 and 25 mg/kg) produced a large but incomplete block (about 50%). DEX had no effect on the responsiveness of the paw on the control side. i.t. injection of 20 micrograms DEX completely blocked heat-hyperalgesia when tested 1 h later; again, the effect was achieved without motor impairment and without any change on the control side. These results suggest that DEX may be useful in the treatment of human neuropathic pain.

Intrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviors in a rat model of peripheral mononeuropathy.

The therapeutic effects of dextrorphan and ketamine, two non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, on neuropathic pain-related behaviors were examined in rats with peripheral mononeuropathy induced by loose ligation of the common sciatic nerve (chronic constrictive injury, CCI). Four daily intrathecal treatments (beginning 1 h after nerve ligation) with dextrorphan or ketamine (12.5-100 nmol) reliably attenuated hyperalgesia to radiant heat and spontaneous pain-related behaviors in CCI rats. Thermal hyperalgesia also was reduced in CCI rats receiving a single intrathecal treatment with either dextrorphan or ketamine (50 and 100 nmol for each compound) on day 3 after nerve ligation when thermal hyperalgesia was well developed. Since both dextrorphan and ketamine are currently utilized in other clinical applications, the results suggest a new therapeutic utility of these 'old' compounds in treatment of neuropathic pain syndromes resulting from peripheral nerve injury.

Comparison of single and combination drug treatment strategies in experimental brain trauma.

Effects of single-drug and combination drug treatments were examined in a model of lateral fluid percussion-induced traumatic brain injury (TBI) in rats. Treatments included the opioid receptor antagonist nalmefene, the thyrotropin releasing hormone (TRH) analog YM14673, the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrorphan, nalmefene + dextrorphan, YM14673 + nalmefene, YM14673 + dextrorphan, and equal volume saline. Single-dose treatment with nalmefene, YM14673, or dextrorphan at 30 min after trauma each significantly improved behavioral recovery at two weeks as compared with vehicle-treated controls, confirming earlier studies with these agents. No combination treatment was superior to treatment with the most effective individual drug alone. Combination treatment with the TRH analog and the NMDA antagonist resulted in significantly less effectiveness than treatment with either drug alone. These findings indicate the need for preclinical studies to examine potential drug-drug interactions in the treatment of central nervous system (CNS) trauma.

Protective effect of N-methyl-D-aspartate antagonists after focal cerebral ischemia in rabbits.

We studied the efficacy of postischemic, systemic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan and dextrorphan in a rabbit model of transient focal cerebral ischemia. Twenty-two rabbits underwent 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4.5 hours of reperfusion before sacrifice. One hour after the onset of ischemia, immediately after removing the arterial clips, the rabbits were blindly assigned to treatment with dextromethorphan (20 mg/kg i.v. loading dose followed by 10 mg/kg/hr maintenance infusion, n = 7), dextrorphan (15 mg/kg i.v. loading dose followed by 15 mg/kg/hr maintenance infusion, n = 7), or an equivalent volume of normal saline alone (n = 8). The maintenance infusion of drugs or saline was continued for the duration of the experiment. The formalin-fixed brains were analyzed with magnetic resonance imaging using coronal T2-weighted images, and ischemic neuronal damage was assessed on standard coronal hematoxylin-and- eosin-stained sections. The area of neocortical ischemic neuronal damage was significantly reduced in the groups treated with dextromethorphan (4.2%, p less than 0.01) and dextrorphan (6.1%, p less than 0.01) compared with the controls (36.2%). Magnetic resonance imaging demonstrated significantly smaller areas of cortical edema in the groups treated with dextromethorphan (14.6%, p less than 0.01) and dextrorphan (8.0%, p less than 0.01) compared with the controls (32.9%). These clinically tested antitussives with NMDA-antagonist properties may have therapeutic value in the treatment of human cerebrovascular disease.